PROJECT SUMMARY/ABSTRACT Rates of substance use disorders (SUDs) and deaths by drug overdose in the United States have reached epidemic levels; yet, the behavioral, pharmacological, and neurobiological determinants of one?s vulnerability to develop a substance use disorder are not well understood. A variety of behavioral and neurochemical phenotypes are thought to predispose rats to developing addiction-like phenotypes based on the following criteria: (1) difficulty stopping drug use; (2) high motivation to take the drug; and, (3) continued drug-taking despite adverse consequences. Though a number of studies suggest that a subset of rats will develop these addiction-like behaviors following long- or intermittent-access to cocaine self-administration, it is important to note that this conceptual framework does not incorporate a core feature of SUDs, high levels of dysregulated drug intake. Indeed, when rats self-administer cocaine under short-access conditions, drug intake tends to be well-regulated, with little inter-subject variability. Conversely, when rats are allowed to self-administer 3,4-methylenedioxypyrovalerone (MDPV; a synthetic cathinone that selectively inhibits uptake at dopamine and norepinephrine relative to serotonin transporters) under short-access conditions, ~40% of them (i.e., ?high-responders?) develop unusually high levels of drug intake (i.e., ~3-fold greater than ?low-responders?). Early studies also suggest that ?high-responders? exhibit high rates of responding during periods of signaled drug unavailability (e.g., drug-seeking), earn more infusions under a progressive ratio (e.g., increased motivation), and are less sensitivity to punishment by foot shock (e.g., continue drug-taking despite adverse consequences). In addition to recapitulating the addiction-like phenotype often reported with long- or intermittent-access to cocaine, because MDPV self-administration also reliably establishes high levels of dysregulated drug-taking, a core feature of addiction, we believe that our model provides a novel and robust approach to study the factors that impact one?s vulnerability to develop a SUD. For instance, mounting evidence suggests that high levels of drug intake and addiction-like patterns of drug taking can result in more robust neuroplastic changes in dopamine (e.g., increases in dopamine D3 receptors) and serotonin (e.g., decreases in serotonin2C receptors) systems that are known to play key roles in mediating the reinforcing effects of drugs. The research project aims to utilize IV self-administration in rats to 1) determine the impact of short-, long-, and intermittent access to MDPV on the development of addiction-like phenotypes in male and female rats; and 2) determine whether the relationship between the dopamine D3 and serotonin2C receptors (expression and function) and the development or severity of addiction-like phenotypes varies as a function of drug (MDPV or cocaine), access condition (short-, long-, intermittent-access), and/or sex. Together, these studies will provide essential information about the causal role of dopamine D3 and serotonin2C receptors and the development or manifestation of dysregulated drug-taking behavior.